Project Summary Multiple sclerosis (MS) is a devastating autoimmune neuroinflammatory disease with a strikingly increasing incidence world-wide, implicating the influence of environmental factors. While genetics of MS are beginning to be understood, they can account for at most ~30% of the disease risk. The remainder of the disease risk is accounted for by environmental factors and gene-by-environment (GE) interactions. Mechanisms of GE in MS are not well understood, and are difficult to study in humans. Mounting evidence implicates a novel environmental risk factor for MS: dysregulation of the gut microbiome. In this application, we propose to take a genome-wide approach to identify gene microbiome interactions in a novel and powerful mouse genetics system. These studies cannot be carried out in humans, and they will provide important mechanistic understanding of GE in autoimmune disease of the CNS, and deliver cause vs. effect distinctions that are lacking in epidemiologic studies.